Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers

Gendron, Tania F.; Blitterswijk, Marka van; Bieniek, Kevin F.; Daughrity, Lillian M.; Jiang, Jie; Rush, Beth; Pedraza, Otto; Lucas, John A.; Murray, Melissa E.; Desaro, Pamela; Robertson, A.; Overstreet, Karen; Thomas, Colleen S.; Crook, Julia E.; Castanedes‐Casey, Monica; Rousseau, Linda; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Boeve, Bradley F.; Graff‐Radford, Neill R.; Rademakers, Rosa; Lagier‐Tourenne, Clotilde; Edbauer, Dieter; Cleveland, Don W.; Dickson, Dennis W.; Petrucelli, Leonard; Boylan, Kevin B.

doi:10.1007/s00401-015-1474-4

Cited by 96 publications

(122 citation statements)

References 43 publications

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“…S5C) were selectively detected in c9ALS fibroblasts. Consistent with previous findings in brain tissues from c9FTD/ALS patients (11), the abundance of poly(GP) proteins correlated with mRNA levels of C9orf72 variant 3 (Fig. S5G) but not of variant 1, variant 2 or total C9orf72 mRNA (Fig.…”

supporting

confidence: 92%

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Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Kramer

Carlomagno

Zhang

et al. 2016

Science

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An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats. We found that targeting the transcription elongation factor, Spt4, selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1, the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci as well as DPR proteins in patient cells. Therapeutic targeting of a single factor to eliminate c9FTD/ALS pathological features offers advantages over approaches that require targeting sense and antisense repeats separately.

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supporting

confidence: 92%

“…S1C). These data are consistent with the prior finding that the abundance of poly(GP) proteins correlate with levels of repeat-containing transcripts (11, 12). Importantly, deleting SPT4 in (GGGGCC) 40 -expressing yeast significantly decreased levels of RAN-translated poly(GP) (Fig.…”

supporting

confidence: 92%

Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Kramer

Carlomagno

Zhang

et al. 2016

Science

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121

146

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“…While we were unable to examine correlations between CSF poly(GP) and repeat length in blood because repeat length data were not available, such an analysis would likely be complicated given the substantial variation in repeat sizes among various tissues from the same individual 33. Furthermore, a previous study has shown no association between CSF poly(GP) and repeat length in blood,14 and we observed no association between poly(GP) levels in the cerebellum or frontal cortex and repeat length in these regions 35. Nonetheless, examining associations between antemortem CSF poly(GP) and repeat size, poly(GP) levels, and levels of other DPR proteins in various neuroanatomical regions will be of interest when postmortem tissue becomes available from a suitable number of cases.…”

Section: Discussioncontrasting

confidence: 53%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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“…Levels of soluble poly(GP) were measured using a previously described sandwich immunoassay using a poly(GP) antibody [21].…”

Section: Gp Immunoassaymentioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers

Cited by 96 publications

References 43 publications

Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

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